Various taxane compounds are known to exhibit anti-tumor activity. As a result of this activity, taxanes have received increasing attention in the scientific and medical community. Primary among these is a compound known as "paclitaxel" which is also referred to in the literature as "taxol". Paclitaxel has been approved for the chemotherapeutic treatment of several different varieties of tumors, and the clinical trials indicate that paclitaxel promises a broad range of potent anti-leukemic and tumor-inhibiting activity. Paclitaxel has the formula: ##STR1##
Paclitaxel is a naturally occurring taxane diterpenoid which is found in several species of the yew (genus Taxus, family Taxaceae). Unfortunately, the concentration of this compound is very low. The species of evergreen are also slow growing. Even though the bark of the yew trees typically exhibit the highest concentration of paclitaxel, the production of one kilogram of paclitaxel requires approximately 16,000 pounds of bark. Thus, the long term prospects for the availability of paclitaxel through isolation are discouraging.
While the presence of paclitaxel in the yew tree is in extremely low concentrations, there are a variety of other taxane compounds, such as Baccatin III, cephalommanine, 10-deacetylbaccatin III, etc., which are also able to be extracted from the yew bark. Some of these other taxane compounds are more readily extracted in higher yields. Indeed, a relatively high concentration of 10-deacetylbaccatin III can be extracted from the leaves of the yew as a renewable resource.
In order to successfully synthesize paclitaxel, convenient access to a chiral, non-racemic side chain and an abundant natural source of a usable baccatin III backbone as well as an effective means of joining the two are necessary. However, the esterification of the side chain to the protected baccatin III backbone is difficult because of the sterically hindered C-13 hydroxyl in the baccatin III backbone which is located within the concave region of the hemispherical protected baccatin III skeleton.
One technique for the semi-synthesis of paclitaxel is found in U.S. Pat. No. 5,684,175 to Sisti et al. In that patent, paclitaxel is synthesized by joining C7-TES baccatin III with N-carbamate protected C2' hydroxyl benzyl-type protected (2R,3S)-3-phenylisoserine, where the C2' hydroxyl is protected by a hydrogenable benzyl-type group such as benzyloxymethyl (BOM) or benzyl. Following the esterification of the protected baccatin III and the protected side chain, the compound may be suitably deprotected, acylated, and further deprotected to yield paclitaxel.
While the existing techniques for synthesizing paclitaxel certainly have merit, there is still a need for improved chemical processes which can produce this anti-cancer compound and intermediates useful in the synthesis and semi-synthesis thereof. The present invention is directed to the synthesis of C-7 CBZ protected baccatin III and analogs thereof through a metal alkoxide intermediate. The C-7 CBZ protected baccatin III can then be esterified with a suitably protected side chain, then the resulting compound deprotected to yield paclitaxel or other analogs.